Metal Mediated Synthesis of 4,5-seco-16-nor-Ergolines

Deirde M.A. Conlon and David A. Widdowson*

Department of Chemistry, Imperial College of
Science, Technology and Medicine, London SW7 2AY, UK.

Abstract

A synthetic approach to the ergoline system based on, inter
alia , chromium mediated 4-functionalisation of indole and
palladium catalysd couplings of an intact ring D moiety is described.
The sequence has been developed to the advanced 4,5-seco
-16-norergoline stage.

Introduction

The synthesis of 4-substituted indoles is a major target of
natural product and pharmaceutical compound synthesis1.
Because of the difficulties of direct 4- substitution in
indoles2 most approaches involve the synthesis of the
indole system presubstituted at C-4 by construction of either the
pyrrolic ring (Scheme 1a)3 or the benzenoid ring (Scheme
1b)4 in a manner which incorporates an appropriate
function, R, at C-4.

Scheme 1

Direct functionalisation at C-4 on the intact indole ring has been
achieved, in a restricted manner, by intramolecular cyclisation from
C-3, in a suitably activated and C-2 blocked substrate (Scheme
2a)5, or, in a more general process, by directed
metallation, notably by thallium, using a C-3 function at the
directing group (Scheme 2b)6. In each case the substituent
at C-3 is essential to the process.

Scheme 2

The direct synthesis of 4-substituted indoles without a
3-substituent has been achieved by activation of the benzenoid ring
to metallation of addition by attachment of a transition metal to
that ring7. Of the metals used, the tricarbonylchromium(0)
moiety has received most attention and an extensive chemistry of
indoletricarbonylchromium(0) complexes have been
reported8. The electron deficiency induced in the ring by
the metal carbonyl unit renders it susceptible to both nucleophilic
addition (Scheme 3a)9 and to deprotonation (Scheme
3b)10 and both of these approaches have been used to
produce 4-substitution11.

Scheme 3

We have sought to exploit the approaches generalised in Schemes 1a
and 3b, in order to gain rapid access to 4-substituted indoles which
contain a preformed ringD of the ergoline molecular framework and so
develop the short synthesis of the ergoline system. We had
established that palladium catalysed coupling to C-4 of indoles could
be seriously inhibited by functionality at C-312,
presumably by a sterically constraining peri-interaction. It was
planned, therefore, to introduce the indole 4-substituent prior to
3-functionalisation and this dictated that carbon 4 (of the ergoline
framework) must be introduced at a late stage, either by attachment
at C-3 followed by closure on to ring D or by incorporation of this
carbon in the ring D fragment. For our initial approach, we chose the
former as expressed retrosynthetically in Scheme 4.

4-Bromoindole was best prepared by a modification of the
Leimgruber-Batcho synthesis14. Thus 2-bromo-6-nitrotoluene
was heated in toluene with DMF dimethyl acetal, DMF and pyrrolidine
at 110°C for 2 h. The resultant enamine was reduced with
titanium trichloride - ammonium acetate in methanol15 to
give 4-bromoindole in 71%yield. Silylation of this with TIPS chloride
- sodium hydride gave the protected indole 6, M = Br, (81%)
required for the ring D coupling step. Lithiation of this (BuLi, THF)
and quenching with triisopropyl borate or trimethylchlorostannane
gave after work up, respectively, the analogous boronic acid
6, M = B(OH)2, (80%) or the stannane 6, M =
SnMe3 (83%) (Scheme 5a).

The basic ring D fragment 5, Y = OH was synthesised in 35%
overall yield from sarcosine according to Shepherd17 in
both the N-methyl series (R = Me) and the N-benzyl series (R = Bn).
These were converted to the analogous sulfonates or halides (Cl, Br)
as shown in Scheme 6.

Scheme 6

Thus the mesylate 5, Y = OSO2Me (89%), the
tosylate 5, Y = OSO2C6H4Me
(42%), and the triflate 5, Y =
OSO2CF3 (31%) were prepared as unstable yellow
oils, which darkened rapidly at room temperature. The halides of the
N-benzyl series were best made by displacement of sulfonate under
Lewis acidic conditions (BF3.OEt2,
BnNMe3+ Hal&endash;)18
which generated the chloride 5, R = Bn, Y = Cl (46%) and
bromide 5, R = Bn, Y = Br (31%) again as unstable yellow oils.
The analogous N-methyl compounds were only isolable in 10% yield and
not further used.

Coupling of ring D to ring A.

With a variety of the ring A and ring D fragments available, the
coupling of these by a tetrakistriphenylphosphinepalladium catalysed
process19 was examined. A test reaction with
3-chlorocyclohex-2-enone and complex 8, followed by
decomplexation of the product with air, gave a total conversion of
74% to the product 9 (60%) together with the desilylated
analogue 10 (14%) (Scheme 7a).

Scheme 7

The analogous reactions with the tetrahydropyridone series
5, R = Bn gave the coupled, desilylated product 11, P =
H in 45%yield, together with some N-silylated material 11, P =
SiiPr3 (5%) and 4-butylated byproduct (5%).

The equivalent reaction of the cuprate derived from the
uncomplexed indoles 6, M = Br, with the
N-benzyltetrahydropyridones 5, gave the same indolic product
11, P = SiiPr3 (45%) in a cleaner
process. Desilylation (TBAF, THF) then gave the indole 11, P =
H (99%). This sequence therefore became the preferred route to the
compounds 11 and 4.

With the ring A &endash; ring D coupling process established, the
required N-methyl series was introduced to the sequence. Coupling of
the 4-metallated N-TIPS indoles 6, M = CuLn or
B(OH)2 or SnMe3, generated previously, with
the pyridones 5, R = Me gave the product 4, P =
SiiPr3 in 31%, 60% and 30% respectively (Scheme
8). The Suzuki type coupling20 of the boronic acid was
therefore established as the preferred method for subsequent
application.

Scheme 8

Synthesis of 4,5-seco -16-norergoline.

The introduction of the one carbon fragment at C-3 was envisaged
as an electrophilic coupling of 4 with Eschenmoser's reagent
(Me2N+=CH2
I&endash;)21. Initially, a series of simple
4-substituted indoles 6, M = H, CH2OAc, CHO,
CH=CHOMe, were examined and found to couple at C-3 with high
efficiency (98%, 98%, 91% and 100% respectively) (Scheme 9a).

Scheme 9

The N-benzyl series analogue 11, however, failed to react,
either with or without the 1-SiiPr3 group. In
the methyl series, no reaction occurred if the N-silyl group was
present but in situ aminomethylenation of the (presumed)
anionic product of fluoride ion desilylation gave the gramine
analogue 3, X = NMe2, P = H in 22% yield (Scheme
9b). A detailed study of this reaction has failed to raise the yield
to a more acceptable level. Thus far, all attempts to generate the
C4&endash;C5 bond (ergoline numbering) have failed and alternative
strategies are under development.

By this means the advanced intermediates 4 and 3
have been prepared in 3 and 4 steps respectively from the readily
available 4-bromoindole in 39% and 9% respectively.